5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence.
Int J Neuropsychopharmacol
; 18(3)2014 Oct 31.
Article
en En
| MEDLINE
| ID: mdl-25522398
ABSTRACT
BACKGROUND:
Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas.METHODS:
Mice lacking the 5-HT reuptake carrier (5-HTT(-/-)) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR-induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos-induced expression) levels.RESULTS:
Although 5-HTT(-/-) mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR-mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT(-/-) mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT(-/-) mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT(-/-) mutants.CONCLUSIONS:
Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT(-/-) mice.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ansiedad
/
Conducta Animal
/
Encéfalo
/
Receptor de Serotonina 5-HT2C
/
Proteínas de Transporte de Serotonina en la Membrana Plasmática
Límite:
Animals
Idioma:
En
Revista:
Int J Neuropsychopharmacol
Asunto de la revista:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Año:
2014
Tipo del documento:
Article